Reactive oxygen species are toxic metabolites of oxygen which are believed to be generated in the brain following head trauma, ischemia, irradiation, metal oxidation, and exposure to neurotoxins. In response to Decade of the Brain Proclamation of 1989, we investigated neurodegenerative mechanisms caused by cytotoxic hydroxyl free radicals (.OH) in the brain and developed a neuroprotective strategy against neuronal injury caused by these cytotoxic free radicals. To study the relevance of reactive oxygen species in causing neurodegeneration, we developed an in vivo assay procedure to detect the generation of short-lived hydroxyl radicals in the brain using an intracranial microdialysis procedure. This in vivo free radical trapping procedure revealed that the dopaminergic neurotoxin MPP+ increased the generation of cytotoxic hydroxyl radicals. Their formation was blocked by the putative neuroprotective agent selegiline (l-deprenyl). Moreover, this preclinical study demonstrated that selegiline preserves or rescues nigral neurons against oxidative stress caused by MPP+. These basic data indicated that selegiline is more effective in the protection of moderately affected than severely damaged brain dopamine neurons. However, the use of selegiline as a neuroprotective antioxidant in Parkinson's disease is currently hampered by difficulties in identifying subclinical cases associated with a 50% or less nigral injury. We are also investigating neuroprotective mechanisms of newly developed free radical scavengers, lipophillic antioxidants, neurotrophin promoters, and calcium antagonists on brain neurons that control cognitive activity.After confirmation of the free radical theory in neurodegenerative disorders and cognition dysfunction, we may be able to identify novel neuroprotective antioxidants for the treatment of progressive disability. Thus, it is feasible that a neurorescue strategy can be formulated to improve the quality of life by halting or slowing progressive neurodegeneration in senescence.